Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a notoriously dismal prognosis. Unfortunately, 80-85% patients are diagnosed with an unresectable, incurable advanced stage disease putting the median survival at <6 months and the overall 5-year survival at <5%.1-3 It is well known that activating mutations of small GTPases such as K-RAS is near universal in PDAC and critical for pathogenesis. Unfortunately even after 3 decades of intense investigation RAS still remains undruggable. In 2013, NCI undertook ?The RAS Initiative? to gain further molecular insight into RAS genes, their protein products, role in cellular signaling and functions in health and disease, underscoring a critical need to identify new molecular regulators of K-RAS activation that can be druggable and devise novel therapeutic strategies to improve dismal outcome in PDAC patients. In this context, defining a role for UBAP2 (Ubiquitin Binding Associated Protein 2), a protein of unknown biological function, as a molecular switch that regulates activation of small GTPases such as KRAS and macropinocytosis in pancreatic cancer is highly innovative. Using antibody-gold nanoconjugates as unique bait, we identified UBAP2 as one of the proteins potentially involved in macropinocytosis in pancreatic cancer. We demonstrate in our preliminary data low UBAP2 expression is correlated with significant increase in overall survival of PDAC patients. We also demonstrate that UBAP2 is overexpressed in pancreatic cancer cell lines and tumor tissues of transgenic KPC mice and PDAC patients. Silencing UBAP2 impairs macropinocytosis in vitro and in vivo, inhibits proliferation, migration and invasion of pancreatic cancer cells in vitro and tumor growth in vivo. Mechanistically, UBAP2 stabilizes the activated forms of small GTPases including Rac1, Cdc42 and K-RAS and protects them from degradation. Furthermore, in association with WAVE2 and Arp2/3, UBAP2 modulates membrane ruffling, critical for fluid phase uptake. Based on these experimental evidences we hypothesize that UBAP2 functions as a molecular switch that regulates activation of small GTPases such as K-RAS, macropinocytosis and pancreatic tumorigenesis. Therefore, establishing role of UBAP2 as a critical regulator of small GTPase activation and macropinocytosis will provide unique opportunities to exploit UBAP2 as a novel therapeutic target against a plethora of human cancers where macropinocytosis and small GTPase activation play a critical role. To test this hypothesis and achieve overall objectives, we will use following specific aims: Specific Aim 1: Molecular characterization of UBAP2 regulated macropinocytosis in pancreatic cancer. Specific Aim 2: Regulation of small GTPases activation by UBAP2. Specific Aim 3: Investigating a role of UBAP2 in KRAS driven pancreatic tumorigenesis. Present application will establish UBAP2 as a new regulator of macropinocytosis, unravel a unique mechanism of KRAS activation and define a role of UBAP2 in normal pancreas development and pancreatic tumorigenesis. These investigations will provide new avenues to target macropinocytosis and KRAS activation that remains elusive so far even after last 30 years of intense investigation.